The presence of food in the mouth activates the parasympathetic nervous system (PNS) and initiates the pre-absorptive release of insulin. To determine the relative effects of neural stimulation of the pancreas and the presence of early insulin on glucose metabolism following a meal, normal weight and obsese subjects (n=6 per group) were admitted into the Clinical Research Center for 4 nights over an 8 day period. Each subject underwent 4 experimental conditions administered in a counter-balanced order: 1) saline infusion; 2) 10 min infusion of insulin simultaneously with meal ingestion (0.24U bolus: 15 mU/m2/min); 3) atropine infusion (0.4mg/m2 bolus; 0.4 mg/m2/hr for 4 hrs); 4) insulin and astropine infusion as above. On each day, after an overnight fast, one chatheter was inserted into an antecubital vein for infusions and an other into a dorsal hand vein to obtain arterialized venous blood samples. Following 3 baseline blood samples, subjects ingested a 600 kcal breakfast. Blood samples were taken every 2 min for 16 min and then every 15 min for 3.5 hrs. Administration of the brief insulin infusion alone had no effect on plasma insulin or glucose in normal weight individuals but lowered levels of both in obese subjects (insulin, t=2.5, P<0.05; glucose, t=2.41, P<0.05). Atropine significantly attenuated plasma glucose (F=1.81, p<0.002) and insulin levels (F=1.50, p<0.01) in both groups, with greater effects on plasma insulin in the obese subjects (p<0.05). The addition of early insulin to atropine further descreased plasma insulin and glucose in the obese compared with atropine alone. Obese subjects exhibited lower plasma glucagon levels compared with normal weight subjects following saline (F=2.7, p<0.0001). In normal weight subjects, atropine attenuated plasma glucagon levels by 112% (F=2.5, P<0.01) leading to a glucagon profile similar to that observed in the obese subjects after saline. No effect of atropine on plasma glucagon was observed in the obese. These data suggest that 1) the PNS plays a significant role in sinulin release following ingestion of a mixed meal 2) the PNS is involved in regulation of basal glucagon levels and 3) Obese subjects may have altered PNS activity contributing to lowered basal glucagon and increased insulin.